Aortic valve stenosis is the major cause of valve disease in the Western world, and the third leading cause of adult heart disease. It is a progressive disorder that worsens with age. Thickening of the aortic valve is followed by calcification that results in further stenosis that ultimately necessitates surgical replacement. A major risk factor for calcific aortic valve disease (CAVD) is bicuspid aortic valve (BAV), which is present in 1?2% of the population, and involves formation of a two- rather than three-valve leaflet. ~35% of individuals with BAV will develop CAVD with age, but some with BAV have thickening even in childhood, requiring intervention. There are no medical treatments available for CAVD patients, and the only clinical option is surgical valve replacement. We reported that heterozygous nonsense mutations in the NOTCH1 (N1) transcription factor cause congenital biscuspid aortic valve (BAV) and severe CAVD and evidence suggests N1 is haploinsufficient in valve endothelial cells (ECs). Induced pluripotent stem cell (iPSC)-derived ECs from several patients with CAVD and N1 haploinsufficiency showed increased expression of pro-osteogenic and inflammatory signaling. Network analysis revealed key nodes that were responsible for much of the gene dysregulation. A chemical screen for the ability to restore expression of 120 dysregulated genes by targeted RNA-sequencing revealed several drugs that restored the network close to the N1+/+ state in human iPSC-ECs, with one, XCT790, showing efficacy in vivo for aortic valve thickening, calcification and stenosis in a mouse model. XCT790 is annotated to function as an inhibitor of estrogen-related receptor alpha (ERR?). We now propose to test the hypotheses that XCT790 prevents aortic valve disease by inhibiting ERR? activity, can treat established disease, and can function in a subset of CAVD patient cells without N1 mutations. The aims are 1) to determine the mechanism of action by which XCT790 corrects disease-associated gene expression and prevents aortic valve disease; 2) to determine if XCT790 can treat established CAVD or prevent neonatal valve stenosis; and 3) to determine if gene dysregulation in primary aortic valve endothelial cells from sporadic CAVD patients with or without genetic variants in NOTCH1 pathway genes is responsive to XCT790. These studies will advance a potential therapeutic to treat a disease that represents an enormous unmet medical need, is characterized by high mortality and morbidity, and for which the only current remedy is a highly invasive surgery.